Project Summary/Abstract: Every year, 20% of the 800,000 Americans that experience a myocardial infarction (MI) consequently develop heart failure, a deadly and costly disease. Several lines of evidence suggest that components of the immune system, specifically myocardial B cells, play a key role in the development of heart failure. Supporting this theory, the PI has recently discovered that small molecule-mediated modulation of a subset of myocardial B cell improves cardiac function after MI. However, our current understanding of myocardial B cell biology is critically lacking, especially in the context of the role B cells play in myocardial adaptation to ischemia-reperfusion (I/R) injury. This lack of knowledge currently hinders the development of B cell-targeted therapies to prevent cardiac dysfunction in heart attack survivors. The two prototypical functions of B cells are antibody production and antigen presentation. However, it is unknown whether either of these two functions underlie the effects of B cells in the heart. Moreover, while the spleen plays a key role in orchestrating B cell response, the relationship between myocardial B cells and the spleen has not been described. In addition, it is unknown whether humans have myocardial B cells similar to those observed in mice. The short-term goal of this proposal is to execute complementary research and career development plans to address these gaps in knowledge and position the PI as a myocardial B cell expert. The long-term goal of this proposal is to use the knowledge gained to facilitate the development of B cell-targeted therapies for heart failure. Here, the PI proposes to test the specific hypothesis that multiple subpopulations of myocardial B cells re-circulate between the heart and the spleen and, in the context of myocardial ischemia- reperfusion injury, modulate the inflammatory response to cardiac damage and adverse cardiac remodeling through an MHC-II antigen presentation-dependent process. The PI has the appropriate background and resources to address the knowledge gaps described, but requires additional mentorship and training in four targeted areas to transition to independence. The PI previously obtained a PhD in developmental biology and has undertaken additional training in basic and translational cardiovascular research. In addition, the PI has completed clinical training in Internal Medicine, Cardiology, Advanced Heart Failure/Cardiac Transplant and he is currently appointed as Instructor of Medicine at Washington University in St Louis. The 5-year career development plan here proposed will provide the PI formal training in four crucial areas: (1) immunology; (2) advanced techniques for the study of cardiac function; (3) advanced molecular biology techniques such as single cell sequencing; (4) enhanced grant writing and leadership skills. At the conclusion of this award period, the PI will have acquired the skills and training necessary to become a leader in the area of myocardial B cell immunology, an under-explored area of scientific investigation that shows great promise for translation into novel therapies.